EP1572195A2 - Natural vitamin e compositions with superior antioxidant potency - Google Patents
Natural vitamin e compositions with superior antioxidant potencyInfo
- Publication number
- EP1572195A2 EP1572195A2 EP03813747A EP03813747A EP1572195A2 EP 1572195 A2 EP1572195 A2 EP 1572195A2 EP 03813747 A EP03813747 A EP 03813747A EP 03813747 A EP03813747 A EP 03813747A EP 1572195 A2 EP1572195 A2 EP 1572195A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- tocopherol
- alpha
- vitamin
- tocotrienols
- gamma
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
- A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
- A61K31/355—Tocopherols, e.g. vitamin E
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/12—Ophthalmic agents for cataracts
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Definitions
- This invention relates to a novel composition
- a novel composition comprising natural d- alpha-tocopherol, mixed natural tocopherols (alpha-tocopherol, beta- tocopherol, gamma- tocopherol, delta- tocopherol), and tocotrienols (alpha- tocotrienol, beta- tocotrienol, gamma- tocotrienol, delta- tocotrienol) having a synergistic antioxidant activity more potent than the antioxidant activity of natural d-alpha-tocopherol.
- Vitamin E is a generic name for a family of four compounds (forms) of tocopherols and four compounds of tocotrienols. All eight compounds have a chromanol ring structure and a side chain. There are four tocopherol forms (alpha, beta, delta, and gamma) with a fully saturated side chain; and four tocotrienol forms (alpha, beta, delta, and gamma) having unsaturated side chains with double bonds at the 3', 7', and 11' positions in the side chain. The . four compounds of both tocopherols and tocotrienols differ from each other in the number and position of methyl groups in the aromatic chromanol ring.
- Alpha-isomers have all three methyl groups in the chromanol ring. Beta and gamma have two methyl groups but at different positions in the aromatic chromanol ring. Delta has only one methyl group in the chromanol ring.
- vitamin E has become synonymous with only alpha-tocopherol.
- the vitamin E compunds are light yellow oils at room temperature and are fairly stable to heat and acid and degrade with alkaline conditions, and when exposed to ultra violet light, and when exposed to the oxygen air.
- vitamin E Foods that are rich in vitamin E include dark green vegetables, eggs, fish, nuts, soy beans, vegetable oils, wheat germ, and whole-grain products. However, foods are commonly depleted of vitamin E due to processing, refining and storage. After absorption in the intestine, vitamin E is transported to the blood circulation by lipoproteins. As a fat-soluble vitamin, vitamin E is amenable for entry and storage in cell membranes.
- Vitamin E is the primary defense against cell membrane and DNA damage and protects LDL and other lipid-rich tissues against oxidation. Vitamin E prevents the oxidation of unsaturated and polyunsaturated fatty acids.
- Tocotrienols due to their unsaturated side chains, provide much stronger antioxidant effects and protect against oxidation of "bad" cholesterol, LDL, which, if oxidized, leads to buildup of plaques in arteries and increased risk of heart attack or stroke.
- the beneficial effects of tocotrienols also include cholesterol lowering, tumor suppressive effect, and inhibition of blood platelet aggregation.
- Reactive oxygen species are of great interest in medicine because of the overwhelming evidence relating them to aging and various disease processes such as atherosclerosis, brain dysfunction, birth defects, cataracts, cancer, immune system decline, rheumatoid arthritis, and inflammatory bowel diseases.
- a complex antioxidant network such as vitamin E, is effective to counteract reactive oxygen species that are detrimental to human life.
- Research studies have indicated that major diseases that afflict humankind worldwide may be preventable by the intake of nutritional supplements, such as antioxidants.
- nutritional supplements such as antioxidants.
- the term "antioxidant" nutritional agent has been applied to a number of specific nutrients; including vitamin E. Antioxidants use therefore has gained popularity to prevent disease and to promote health. These compounds are readily available, and non-toxic.
- Antioxidants function by neutralizing the harmful effects of free radicals. Free radicals are unstable, highly reactive molecules that circulate in the bloodstream. Some of these free radicals result from lifestyle factors like environmental stress and strenuous exercise, as well as natural processes like aging. To become chemically stable, free radicals take electrons from other molecules in the body, a process that causes cell damage (oxidative damage). Antioxidants prevent oxidative damage by donating electrons to free radicals. As a fat-soluble vitamin, Vitamin E is amenable for entry and storage in cell membranes to react with free-radical molecules and reduce the damage they cause.
- Vitamin E protects the skeletal muscles, nervous system, and retina of the eye from oxidation. Vitamin E is essential for normal immune function. Vitamin E mitigates the prostaglandin driven severity of inflammation, PMS and circulatory disorders. Vitamin E may reduce the toxicity of metals and protect against free radical promoting environmental pollutants such as ozone, oxides of nitrogen, drugs, alcohol and smoking. Aging is essentially oxidative deterioration of tissues. Since vitamin E can prevent or slow down reactions of such oxidative damage, vitamin E may slow the aging process. The importance of antioxidants stems from the number of diseases where they play a preventive role, such as heart disease, cancer, and eye disease.
- vitamin E ranging from 50 to 400 International Units (LU.) per day did not show any adverse effects in double-blind clinical studies.
- the recommended daily amount (RDA) is 8 to 10 mg per day for healthy adults.
- 400 LU. soft gelatin capsules are the most popular dosage from vitamin E.
- a person needs to consume 450 g of sunflower seeds, 2.2 kg of wheat germ or 1.9 liters of corn oil totaling 8,000 calories daily.
- Fat soluble vitamins, like vitamin E, are found in foods associated with lipids and are absorbed from the intestine with dietary fats. Therefore, vitamin E intake is recommended with a meal and normally 20 to 40 percent of the ingested vitamin E is absorbed.
- Gamma-tocopherol the principle form of vitamin E in the diet, has been scientifically proven to enhance the health benefits of alpha-tocopherol, and is superior in promoting cardiovascular, brain, and immune health.
- Gamma-tocopherol was also found to be superior to alpha-tocopherol in protecting cells against peroxynitrite, a harmful chemical that alters DNA and causes cancer.
- a nested case-control study involving men who developed prostate cancer and matched control subjects showed that men with high blood levels of gamma tocopherol had a significant reduction in the risk of developing prostate cancer.
- the study also found a significant protective association for high levels of selenium and alpha tocopherol only in men with high gamma- tocopherol concentration.
- gamma-tocopherol and alpha-carotene were found to be significantly lower in plasma of coronary heart disease patients compared to healthy people, suggesting that the plasma level of gamma-tocopherol might represent a marker of atherosclerosis in humans.
- gamma-tocopherol was found to enhance the bio- potency of alpha-tocopherol.
- Gamma-Tocopherol induced a marked increase in alpha-tocopherol concentrations in the serum and in nerve tissues, heart, liver, and muscle in rats fed diets containing both gamma-tocopherol and alpha-tocopherol more than those fed a diet containing alpha-tocopherol alone.
- gamma-Tocotrienol was also found to prevent development of increased blood pressure, to reduce lipid peroxidation in plasma and blood vessels, and to enhance total antioxidant status including superoxide dismutase activity.
- a recent study also showed that supplementation with 100 mg/day tocotrienol- rich fraction of rice bran for a month resulted in a significant reduction in total cholesterol, LDL-cholesterol and triglycerides.
- compositions comprising a full spectrum of all forms of tocopherols and tocotrienols will provide greater health benefits of vitamin E than the only form alpha-tocopherol.
- New compositions of vitamin E comprising all forms of vitamin E were formulated to meet certain criteria: the desired 400 LU., higher antioxidant potency than alpha-tocopherol, and comparable cost to the commercially marketed natural vitamin E.
- the ORAC method utilizes a peroxyl radical generator and beta- phycoerythrin protein as an indicator of oxidation by measuring the fluorescence of the protein.
- the ORAC values are expressed as micromoles of Trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-onecarboxylic acid) equivalents per liter of the sample and Trolox shows total inhibition of the peroxyl radical action.
- the ORAC assay is a widely accepted method in the world for identifying the antioxidant potential in a sample.
- the samples can be a pure compound, blood plasma, various tissues and foods such as fruits, vegetables, or dietary supplements.
- the total antioxidant capacity is reflected from various antioxidants present in the sample and their interactions.
- the advantage of this assay is that it helps quantify the antioxidant potential value of a sample compared to other commercial samples.
- natural vitamin E d-alpha-tocopherol
- additional vitamin E compounds specifically natural mixed tocopherols (alpha-, beta-, gamma-, delta-) and tocotrienols (alpha-, beta-, gamma-, delta-)
- ORAC oxygen radical absorbance capacity
- This invention relates to formulations comprising all forms of natural tocopherols and tocotrienols with enhanced antioxidant activities. These formulations were designed to provide 400 IU, based on one mg d-alpha- tocopherol equals 1.49 IU.
- the invention further relates to a soft gelatin formulation containing natural vitamin E as d-alpha-tocopherol, mixed tocopherols in the form Alpha, Gamma, Delta, Beta, and tocotrienols, with inseparable tocopherols, in the form of Alpha, Gamma, Delta, Beta.
- the formulation is contained in a soft gelatin capsule composed of gelatin, glycerin, and water.
- the formulation is designed to provide antioxidant protection for the cell lipid membrane, and protection against heart disease, cancer, and eye disease.
- antioxidant activities of natural d-alpha-tocopherol, mixed tocopherols and tocotrienols, and formulations comprising all forms of vitamin E were determined employing an improved oxygen radical absorbance capacity (ORAC) assay using fluorescein (FL) as a fluorescent probe, randomly methylated ⁇ -cyclodextrin (RMCD) to enhance solubility of lipophilic antioxidants in aqueous medium, 2,2' - azobis (2-amidino-propane) dihydrochloride (AAPH) as peroxyl radical generator, and Trolox as a standard in 75 mM phosphate buffer.
- ORAC oxygen radical absorbance capacity
- FL fluorescein
- RMCD randomly methylated ⁇ -cyclodextrin
- AAPH 2,2' - azobis (2-amidino-propane) dihydrochloride
- Trolox as a standard in 75 mM phosphate buffer.
- Vitamin E forrnulations comprising alpha-, beta-, delta-, and gamma- forms of tocopherols and tocotrienols with enhanced antioxidant activities were developed. All of these formulations provide 400 LU., based on one mg of d-alpha-tocopherol equals 1.49 LU. Some of these formulations showed antioxidant activities superior to d-alpha-tocopherol.
- This patent discloses formulations comprising all forms of tocopherols and tocotrienols with enhanced antioxidant activities. These formulations provide 400 U., based on one mg d-alpha-tocopherol equals 1.49 LU.. Novel formulations of vitamin E comprising a full spectrum of all forms of vitamin E, which possess significantly higher antioxidant activity than alpha-tocopherol are disclosed. Other features and advantages of the present invention will become more apparent from the following detailed description, which illustrate, by way of example, the principles of the invention.
- the antioxidant activity, commonly referred to as oxygen radical absorbance capacity (ORAC), of a lipophilic substance was measured employing a newly developed assay.
- This assay is based on the use of: (a) fluorescein (FL) as the fluorescent probe, (b) randomly methylated ⁇ - cyclodextrin (RMCD) as a molecular host to enhance the solubility of lipophilic antioxidants in aqueous solution, (c) 2,2'-azobis (2-amidino- propane) dihydrochloride (AAPH) as a peroxyl radical generator, and (d) 6- hydroxy-2,5,7,8-tetramethyl-2-carboxylic acid (Trolox) as a standard in 75 mM phosphate buffer (pH 7.4).
- vitamin E formulations comprising all compounds of tocopherols and tocotrienols were determined employing an improved oxygen radical absorbance capacity (abbreviated ORACFL-LIPO) assay using fluorescein (FL) as the fluorescent probe, randomly methylated ⁇ - cyclodextrin (RMCD) as the water solubility enhancer for lipophilic antioxidants in 75 mM phosphate buffer (pH 7.4).
- ORACFL-LIPO oxygen radical absorbance capacity
- FL fluorescein
- RMCD randomly methylated ⁇ - cyclodextrin
- the indicator FL In the presence of peroxyl radicals derived from AAPH, the indicator FL gradually loses its fluorescence.
- the antioxidant activity of a substance is measured by its ability to retain the fluorescence of FL in the presence of peroxyl radicals. The net protection of FL was measured as previously described by Ou et al. Chemicals and Apparatus
- Randomly methylated ⁇ -cyclodextrin was purchased from Cyclolab R&D Ltd. (Budapest, Hungary). Fluorescein (FL) and 6-hydroxy- 2,5,7,8-tetramethyl-2-carboxylic acid (Trolox) were purchased from Aldrich (Milwaukee, I).2,2' - azobis (2-amidino-propane) dihydrochloride (AAPH) was obtained from Wako Chemicals USA (Richmond, VA). 87% d-alpha- Tocopherol (containing 13% soy bean oil) and 70% mixed tocopherols (containing 30% soy bean oil) were purchased from Archer Daniels Midland.
- Each gram of 70% mixed tocopherols contains 114mg d-alpha-tocopherol, l lmg d-beta-tocopherol, 457mg d-gamma-tocopherol, and 131mg d-delta- tocopherol.
- Tocotrienols oil was purchased from Oryza Oil and Fat Chemical Co. in Japan. Tocotrienols oil contains 35 % total tocopherols and tocotrienols (12.6 % gamma- tocotrienol, 7.2 % alpha-tocotrienol, and 12.7 % alpha- tocopherol). Palm oil containing 50% total tocopherols and tocotrienols (10% alpha-tocopherol, 11% alpha-tocotrienol, 20% gamma-tocotrienol, and others) was obtained from Carotech (Edison, New Jersey).
- sample solution was dissolved in 20 mL of acetone.
- An aliquot of sample solution was appropriately diluted with 7% RMCD solvent (w/v) made in a 50% acetone-water mixture (v/v) and was shaken for 1 hr at room temperature on an orbital shaker at 400 rpm.
- the sample solution was ready for analysis after further dilution with 7% RMCD solvent.
- the automated ORAC assay was carried out on a COBAS FARA II spectrofluorometer centrifugal analyzer as previously described (9). With the exception of samples and Trolox standards, which were made in 7% RMCD solvent, all other reagents were prepared at 75 mM phosphate buffer (pH 7.4). In the final assay mixture (0.4 mL total volume), FL (6.3 x 10 "8 M) was used as a target of free radical attack and AAPH (1.28 x 10 "2 M) was used as a peroxyl radical generator.7% RMCD was used as the blank, and Trolox (12.5, 25, 50, and 100 ⁇ M) was used as the control standard.
- the analyzer was programmed to record the fluorescence of FL every minute after the addition of AAPH. All measurements were expressed relative to the initial reading. Final results were calculated using the differences of areas under the FL decay curves between the blank and a sample. These results were expressed as micromoles Trolox equivalent (TE) per gram, as previously described by Ou et al. .
- the antioxidant activity, commonly referred to as oxygen radical absorbance capacity (ORAC), of a lipophilic substance was measured employing a newly developed assay.
- This assay is based on the use of: (a) fluorescein (FL) as the fluorescent probe, (b) randomly methylated ⁇ - cyclodextrin (RMCD) as a molecular host to enhance the solubility of lipophilic antioxidants in aqueous solution, (c) 2,2'-azobis (2-amidino- propane) dihydrochloride (AAPH) as a peroxyl radical generator, and (d) 6- hydroxy-2,5 ,7,8-tetramethyl-2-carboxylic acid (Trolox) as a standard in 75 mM phosphate buffer (pH 7.4).
- the indicator FL In the presence of peroxyl radicals derived from AAPH, the indicator FL gradually loses its fluorescence.
- the antioxidant activity of a substance is measured by its ability to retain the fluorescence of FL in the presence of peroxyl radicals. The net protection of FL was determined as previously described by Ou et al. .
- the ORAC value was calculated as ⁇ mole Trolox equivalent per gram sample ( ⁇ mole TE/g); one gram of sample has antioxidant activity equals to how many ⁇ mole Trolox.
- Tables (1) and (2) list the ORAC data expressed in ⁇ mole Trolox equivalent (TE) per gram of tested antioxidant sample.
- the formulations in Table (2) differ from those in Table (1) in that the Table (2) formulations further include Palm Oil and there is a slight modification in the ingredients of Formula 2 in Table (2) as compared to Formula 2 in Table (1).
- the results of data in Table (1) showed that the synthetic vitamin E acetate showed no antioxidant activity under current experimental conditions, supporting the essential role of the phenolic type hydroxyl for radical trapping antioxidant activity of vitamin E.
- the IUs (International Unit) of a sample are based on one mg of alpha-tocopherol equals 1.49 IU.
- Formula- 1 307 mg alpha-tocopherol (87%), 15 mg tocotrienols (30%), 200 mg mixed tocopherols (70%).
- Formula-2 293 mg alpha-tocopherol (87%), 10 mg tocotrienols (30%), 150 mg mixed tocopherols (70%).
- Formula-3 303 mg alpha-tocopherol (87%), 10 mg tocotrienols (30%), 50 mg mixed tocopherols (70%).
- Formula-4 316 mg alpha-tocopherol (87%), 16.5 mg tocotrienols (30%).
- Formula-2 293 mg alpha-tocopherol (87%), 10 mg tocotrienols (30%), 150 mg mixed tocopherols (70%).
- Formula-2a 293 mg alpha-tocopherol (87%), 10 mg tocotrienols (30%), 160 mg mixed tocopherols (70%).
- Formula-2ab 293 mg alpha-tocopherol (87%), 10 mg tocotrienols (30%), 175 mg mixed tocopherols (70%).
- Formula-2ac 293.5 mg alpha-tocopherol (87%), 4.3 mg tocotrienols (50%), 160 mg mixed tocopherols (70%).
- ⁇ mole TE/400IU ⁇ mole TE/g x total weight in grams of vitamin E formula which gives 400 IU
- Table (1) revealed that alpha-tocopherol (87%) had a value of 1,293 ⁇ mole Trolox equivalent (TE) per gram, from this data one can calculate the ⁇ mole TE of 400 LU. of alpha-tocopherol (87%) to be 398 (307.7 mg alpha-tocopherol is equivalent to 400 LU.).
- the ⁇ mole TE per 400 LU. of each vitamin E formula can be calculated, and the results are given in table (1).
- vitamin E has generally been associated with its well-defined antioxidant property, specifically against lipid peroxidation in biological membranes. Therefore, it is anticipated that, enhancing the antioxidant property of vitamin E as well as the full spectrum of various vitamin E forms might provide better health benefits than just alpha- tocopherol.
- antioxidant activities of alpha-tocopherol, mixed tocopherol and tocotrienols, and vitamin E formulations comprising all forms of tocopherols and tocotrienols were determined employing an oxygen radical absorbance capacity assay suitable for lipophilic antioxidants. The results of this study clearly indicate that mixed tocopherols possess higher antioxidant activity than d-alpha-tocopherol.
- Vitamin E formulations providing 400 I.U., comprising various forms of tocopherols and tocotrienols with enhanced antioxidant activities were developed. Some of these formulations showed antioxidant activities superior to d-alpha-tocopherol.
- Formula- 1 and Formula-2 were found to possess a much higher ORAC value than that of natural vitamin E (d-alpha-tocopherol).
- Formula-3 also showed an increase (25%) in its antioxidant activity as compared to alpha- tocopherol.
- Formula-4 showed slightly higher antioxidant activity that alpha- tocopherol.
- Formulae- 1, -2, -3 contain alpha-tocopherol, mixed-tocopherols and tocotrienols, whereas Formula-4 contains only alpha-tocopherol and tocotrienols.
- Formula- 1 and Formula-2 is calculated to be 24 % and 21 %; respectively. These values are in accordance with the recommended amounts of gamma-tocopherol in vitamin E supplement . This study was published in Proceedings of the national Academy of Science, USA (1997), and suggested that vitamin E supplement should have at least 20 % gamma-tocopherol. Formula-3, on the other hand, contains only 9 % gamma-tocopherol.
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Abstract
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Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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US321318 | 2002-12-17 | ||
US10/321,318 US7329688B2 (en) | 2002-12-17 | 2002-12-17 | Natural vitamin E compositions with superior antioxidant potency |
PCT/US2003/040398 WO2004056348A2 (en) | 2002-12-17 | 2003-12-17 | Natural vitamin e compositions with superior antioxidant potency |
Publications (2)
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EP1572195A2 true EP1572195A2 (en) | 2005-09-14 |
EP1572195B1 EP1572195B1 (en) | 2007-08-29 |
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EP03813747A Expired - Lifetime EP1572195B1 (en) | 2002-12-17 | 2003-12-17 | Natural vitamin e compositions with superior antioxidant potency |
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US (4) | US7329688B2 (en) |
EP (1) | EP1572195B1 (en) |
AT (1) | ATE371447T1 (en) |
AU (1) | AU2003301069B2 (en) |
DE (1) | DE60316024D1 (en) |
WO (1) | WO2004056348A2 (en) |
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US6716451B1 (en) * | 1999-11-30 | 2004-04-06 | Soft Gel Technologies, Inc. | Formulation and delivery method to enhance antioxidant potency of vitamin E |
AU2002327517B2 (en) * | 2001-08-21 | 2008-04-17 | Johnson & Johnson Consumer Companies, Inc. | Tocopherol enriched compositions and amelioration of inflammatory symptoms |
US20030144219A1 (en) * | 2001-11-15 | 2003-07-31 | Phinney Stephen Dodge | Formulations and methods for treatment or amelioration of inflammatory conditions |
US20040048919A1 (en) * | 2002-07-02 | 2004-03-11 | Dreon Darlene M. | Compositions and methods for reduction of inflammatory symptoms and/or biomarkers in female subjects |
US7329688B2 (en) * | 2002-12-17 | 2008-02-12 | Soft Gel Technologies, Inc. | Natural vitamin E compositions with superior antioxidant potency |
US20050112078A1 (en) * | 2003-11-13 | 2005-05-26 | Sekhar Boddupalli | Plant-derived protein extract compositions and methods |
US20080038316A1 (en) * | 2004-10-01 | 2008-02-14 | Wong Vernon G | Conveniently implantable sustained release drug compositions |
US20070021497A1 (en) * | 2005-07-11 | 2007-01-25 | The Fruitful Yield | Vitamin e compositions |
BRPI0613631A8 (en) * | 2005-07-18 | 2017-12-26 | Univ Massachusetts Lowell | nanoemulsion and method, |
HUP0500975A2 (en) * | 2005-10-25 | 2008-02-28 | Arpad Tosaki | Process for producing of extract of sour cherry seed, use of extract for producing of medicament and medicaments consist extract |
US9486408B2 (en) | 2005-12-01 | 2016-11-08 | University Of Massachusetts Lowell | Botulinum nanoemulsions |
ES2700983T3 (en) | 2012-06-08 | 2019-02-20 | Univ Ohio State | Treatment of cicatricial injury using tocotrienol |
CN110225975A (en) | 2016-08-23 | 2019-09-10 | 阿库斯股份有限公司 | For treating the composition and method of non-age-dependent hearing impairment in people experimenter |
JP2019535829A (en) | 2016-11-21 | 2019-12-12 | エイリオン セラピューティクス, インコーポレイテッド | Transdermal delivery of large drugs |
WO2021168362A1 (en) | 2020-02-21 | 2021-08-26 | Akouos, Inc. | Compositions and methods for treating non-age-associated hearing impairment in a human subject |
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2003
- 2003-12-17 WO PCT/US2003/040398 patent/WO2004056348A2/en active IP Right Grant
- 2003-12-17 AU AU2003301069A patent/AU2003301069B2/en not_active Expired
- 2003-12-17 DE DE60316024T patent/DE60316024D1/en not_active Expired - Lifetime
- 2003-12-17 EP EP03813747A patent/EP1572195B1/en not_active Expired - Lifetime
- 2003-12-17 AT AT03813747T patent/ATE371447T1/en not_active IP Right Cessation
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2005
- 2005-12-19 US US11/311,533 patent/US7449491B2/en not_active Expired - Lifetime
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Title |
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See references of WO2004056348A2 * |
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US7329688B2 (en) | 2008-02-12 |
US20060093664A1 (en) | 2006-05-04 |
EP1572195B1 (en) | 2007-08-29 |
WO2004056348A2 (en) | 2004-07-08 |
DE60316024D1 (en) | 2007-10-11 |
US20090156664A1 (en) | 2009-06-18 |
ATE371447T1 (en) | 2007-09-15 |
WO2004056348A3 (en) | 2004-09-10 |
US20110251274A1 (en) | 2011-10-13 |
US7449491B2 (en) | 2008-11-11 |
AU2003301069A1 (en) | 2004-07-14 |
US7989493B2 (en) | 2011-08-02 |
AU2003301069B2 (en) | 2010-11-18 |
US20040116512A1 (en) | 2004-06-17 |
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